The growth and development of normal tissues is achieved by programmed cell proliferation, differentiation and cell death. Cell proliferation and differentiation are required for the formation of new cells and tissues. Conversely, programmed cell death, also referred to as apoptosis, is required to remove existing cells, including immature or damaged cells. Apoptosis naturally occurs in virtually all tissues of the body. Apoptosis plays a critical role in tissue homeostasis, that is, it ensures that the number of new cells produced are correspondingly offset by an equal number of cells that die. For example, the cells in the intestinal lining divide so rapidly that the body must eliminate cells after only three days in order to prevent the overgrowth of the intestinal lining.
The disruption of the genetic program, by either abnormally increasing or decreasing rate of cell proliferation and/or apoptosis can result in abnormal tissue development. For example, decreases in cell proliferation below normal levels can lead to immature tissues and other tissue abnormalities. Increases in cell proliferation above normal levels are thought to be major events in the development of neoplasia and cancer, as well as other cell proliferative disorders. Abnormal increases in apoptosis can also lead to precancerous lesions. Precancerous lesions include lesions of the breast (that can develop into breast cancer), lesions of the prostate (that can develop into prostate cancer) or skin (that can develop into malignant melanoma or basal cell carcinoma), colonic adenomatous polyps (that can develop into colon cancer), and other such neoplasia. Such lesions exhibit a strong tendency to develop into malignant tumors or cancer.
Precancerous lesions can result from an accumulation of insults to existing cells in various tissues of the body. Such insults can include exposure to sunlight, radiation, mutagens and carcinogens normally found in the diet, chemicals such as pesticides, herbicides, preservatives, and the like. These insults can result in the accumulation of mutations in the cells, which can lead to hyperplastic conditions (i.e., abnormal increases in cell number), such as, for example, hyperplasia of liver, kidney, spleen, thymus, intestine, lung or prostate tissues. The down-regulation of apoptosis can also lead to the accumulation of cells in these hyperplastic conditions.
An abnormal increase in apoptosis can interfere with normal development and/or differentiation of tissues. For example, apoptosis is required during pregnancy and for maturation of the male reproductive tract tissues. An abnormal increase in apoptosis can also interfere with the formation of new cells and tissues, thereby preventing normal tissue maturation or development.
Thus, there is a need for methods of modulating apoptosis by administering agonists or antagonists of apoptosis. In particular, there is a need for methods of treating conditions associated, directly or indirectly, with abnormally high or low rates of apoptosis. The present invention satisfies this need by providing methods for the administration of relaxin agonists or antagonists to treat relaxin-associated tissue abnormalities by modulating apoptosis in such tissues.